Original Research ajog.

org

OBSTETRICS
Intrapartum magnesium sulfate is associated with
neuroprotection in growth-restricted fetuses
Elizabeth L. Stockley, MBBS; Joseph Y. Ting, MBBS; John C. Kingdom, MD; Sarah D. McDonald, MD, MSc;
Jon F. Barrett, MD; Anne R. Synnes, MDCM, MHSc; Luis Monterrosa, MD; Prakesh S. Shah, MD, MSc;
on behalf of the Canadian Neonatal Network, Canadian Neonatal Follow-up Network, and Canadian Preterm
Birth Network Investigators*

BACKGROUND: Intrapartum magnesium sulfate administration is
recommended for fetal neuroprotection in women with imminent very
preterm birth. However, previous studies have not included or separately
analyzed the outcomes of pregnancies with fetal growth restriction that
were treated with intrapartum magnesium sulfate.
OBJECTIVE: We sought to evaluate the neonatal and neuro-
developmental outcomes of growth-restricted fetuses born <29 weeks’
gestation and exposed to maternal intrapartum magnesium sulfate.
STUDY DESIGN: We conducted a retrospective cohort study of infants
born <29 weeks’ gestation from 2010 through 2011, admitted to
participating Canadian Neonatal Network units, and followed by the Ca-
nadian Neonatal Follow-up Network centers. Growth restriction was
defined either as estimated fetal or actual neonatal birthweight <10th
percentile according to fetal or neonatal growth standards for gestational
age and sex, respectively. Infants exposed to intrapartum magnesium
sulfate were compared with unexposed infants. The primary outcome was
composite of death or significant neurodevelopmental impairment at
18e36 months’ corrected age. Secondary outcomes were death or any
neurodevelopmental impairment at 18e36 months’ corrected age.
Neonatal morbidities were also compared.
RESULTS: Of the 336 growth-restricted fetuses, 112 (33%) received
magnesium sulfate and of the 177 growth-restricted infants, 61 (34%)
received magnesium sulfate. Administration of magnesium sulfate was at
the discretion of the treating physician. Intrapartum magnesium sulfate
was associated with reduced odds of composite of death or significant
neurodevelopmental impairment for infants classified according to both
fetal standards (adjusted odds ratio, 0.42; 95% confidence interval,
0.22e0.80) and neonatal standards (adjusted odds ratio, 0.44; 95%
confidence interval, 0.20e0.98).
CONCLUSION: Intrapartum administration of magnesium sulfate to
women with growth-restricted fetuses born <29 weeks’ gestation was
associated with reduced odds of composite of death or significant neu-
rodevelopmental impairment.
Key words: cerebral palsy, extremely preterm birth, mortality, motor
performance, neurodevelopmental impairment, small for gestation fetuses

Introduction
Administration of intrapartum magne-
sium sulfate is recommended for fetal
neuroprotection in women presenting
with imminent preterm birth at <32
weeks’ gestation.1 This practice is sup-
ported by meta-analyses that showed
administration of intrapartum magne-
sium sulfate was associated with a
reduced risk of cerebral palsy (CP) in
preterm infants.2e4 However, previous
clinical trials did not include or analyze
the outcomes of pregnancies with fetal
growth restriction.5e9 It is unclear
whether administration of magnesium
Cite this article as: Stockley EL, Ting JY, Kingdom JC,
et al. Intrapartum magnesium sulfate is associated with
neuroprotection in growth-restricted fetuses. Am J Obstet
Gynecol 2018;219:606.e1-8.
0002-9378/$36.00
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.09.010
sulfate to pregnancies with fetal growth
restriction can reverse the consequences
of adverse brain growth associated with
fetal growth restriction as some of the
processes for neuronal injury may have
been established already in such
fetuses.10e12 Moreover, borderline high
ionized magnesium levels in cord blood
were observed in growth-restricted fe-
tuses when compared to healthy term
newborns, though neither group was
exposed to intrapartum magnesium
sulfate.13 Thus, intrapartum magnesium
sulfate could lead to levels of magnesium
that are neurotoxic in growth-restricted
fetuses. To our knowledge, there are no
published studies evaluating the safety
and long-term effects of intrapartum
magnesium sulfate in growth-restricted
fetuses.12 Thus, our objective was to
compare the neonatal and neuro-
developmental outcomes of growth-
restricted fetuses born <29 weeks’
gestation who received intrapartum
magnesium sulfate for neuroprotection
with those who did not receive magne-
sium sulfate.
Materials and Methods
Design and participants
We conducted a retrospective cohort
study using data collected for the Cana-
dian Neonatal Network (CNN) and the
Canadian Neonatal Follow-up Network
(CNFUN) as part of our wider initiative,
the Canadian Preterm Birth Network.14
Growth-restricted infants of <29
weeks’ gestation born from Jan. 1, 2010,
through Sept. 30, 2011, who were
admitted to one of the tertiary neonatal
intensive care units (NICUs) partici-
pating in the CNN and were assessed in
neurodevelopmental follow-up clinics at
18e36 months’ corrected age were
included. We have included only infants
<29 weeks’ gestation as these infants are
at very high risk of neurodevelopmental
impairment (NDI) so we have targeted
to have standardized follow-up of such
infants in a national cohort in Canada.

606.e1 American Journal of Obstetrics & Gynecology DECEMBER 2018

ajog.org OBSTETRICS Original Research

Administration of magnesium sulfate

AJOG at a Glance was at the discretion of the treating
Why was this study conducted? physician. Admission severity of illness
This study was conducted to evaluate the neuroprotective effects and safety of was characterized by the Score for
intrapartum magnesium sulfate in growth-restricted fetuses. Neonatal Acute Physiology-II.23
Neonatal morbidities evaluated were
Key findings intraventricular hemorrhage defined
We found that intrapartum magnesium sulfate given to mothers of growth- according to Papile classification;24
restricted infants of <29 weeks’ gestation was associated with reduced odds of nosocomial infection, defined as the
death or significant neurodevelopmental impairment at 18e36 months’ cor- presence of a pathogenic organism in
rected age. blood or cerebrospinal fluid in a symp-
tomatic infant >2 days of age; bron-
What does this add to what is known? chopulmonary dysplasia, defined as
This study furthers our knowledge of the beneficial effects of intrapartum mag- receipt of oxygen or respiratory support
nesium sulfate for neuroprotection in growth-restricted extremely preterm in- at 36 weeks’ postmenstrual age or at
fants of <29 weeks’ gestation. discharge; necrotizing enterocolitis,
defined according to the Bell criteria;25
Growth restriction was defined in 2 with GMFCS score
I or any BSID-III and severe retinopathy of prematurity
ways: estimated fetal weight and actual component score of <85 in any (ROP), defined as stage
3 or ROP
birthweight <10th percentile according domain.19 Sensory impairments were requiring treatment with laser or anti-
to fetal15 and neonatal16 growth stan- unlikely affected by magnesium sulfate; vascular endothelial growth factor.26
dards, respectively. We assumed that thus, vision and hearing impairments At 18e36 months’ corrected age,
actual birthweight was the same as esti- were not included in the definition of children were assessed at affiliated
mated fetal weight because when mag- NDI. Target neurodevelopmental assess- CNFUN sites by specialized clinicians
nesium sulfate is administered the ment age was 18e21 months’ corrected whenever possible, and 6% of assess-
maternal care provider is only aware of age. A few difficult-to-track participants ments were by community health care
the estimated fetal weight. We also were seen >21 months; median assess- professionals. The assessment included a
analyzed data using neonatal classifica- ment age was 18 months’ corrected age. standardized history, physical and
tion of small for gestational age as this Common neonatal morbidities defined neurological examinations, and admin-
included the correct birthweight infor- below were also compared. istration of the BSID-III test to obtain
mation. Infants were subdivided into 2 cognitive, language, and motor scores. In
groups: infants exposed to intrapartum Data collection cases where the child could not be tested,
magnesium sulfate and infants not Patient data were collected by the CNN the BSID-III Adaptive Behavior ques-
exposed to intrapartum magnesium and CNFUN across all centers using tionnaires were administered. A diag-
sulfate. Infants with major congenital or standard manuals of operations and nosis of CP was made using standard
chromosomal anomalies, planned palli- definitions.20,21 The CNN database was definitions27 and if CP was present, the
ative care prior to birth, or missing data shown to have high consistency and degree of functional impairment was
were excluded. Mount Sinai Hospital’s reliability.22 Eligible infants were identi- classified using the GMFCS.
Research Ethics Board and the steering fied within the CNN database and linked
committees of CNN and CNFUN to the CNFUN database using a unique Statistical analysis
approved data collection and analyses. identifier. The CNN covered 28 NICUs Maternal and infant characteristics,
and CNFUN all 26 follow-up clinics as well as the primary and secondary
Outcomes during the study period encompassing outcomes, were compared among in-
The primary outcome was composite of w90% of eligible infants born during fants exposed and unexposed to intra-
death or significant NDI (sNDI) defined the study period in Canada. partum magnesium sulfate. Frequency
as any of the CP with Gross Motor Variables obtained from the CNN (percentage), mean (SD), or median
Function Classification System database were: (1) growth restriction, (interquartile range) were reported.
(GMFCS)17 score
III; or Bayley Scales of defined as both estimated and actual Differences were assessed by Pearson c2
Infant and Toddler Development-third weight <10th percentile for gestational for categorical variables, and Student t
edition (BSID-III)18 motor, language, age and sex according to fetal and test or Wilcoxon rank test for continuous
cognitive, or general adaptive composite neonatal growth standards as described variables. Multivariable logistic analyses
scores of <70; or severe developmental above; (2) exposure of intrapartum were applied for primary and secondary
delay that precluded the use of BSID-III magnesium sulfate; (3) maternal and outcomes. Adjusted odds ratios (aORs)
for assessment at 18e36 months’ cor- neonatal characteristics; (4) common and 95% confidence intervals were esti-
rected age. Secondary outcomes were neonatal morbidities; and (5) mortality, mated. Confounding factors included
death or any NDI defined as any of the CP both in the NICU and postdischarge. the following: maternal hypertension,

DECEMBER 2018 American Journal of Obstetrics & Gynecology 606.e2

Original Research OBSTETRICS
FIGURE
Flow diagram of the study population
Flow diagram of study population.
MgSO4, magnesium sulfate; NICU, neonatal intensive care unit.
Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.
cesarean delivery, multiple gestations,
gestational age, male sex, and Score for
Neonatal Acute Physiology-II score >20.
All analyses were conducted using soft-
ware (SAS 9.3; SAS Institute Inc, Cary,
NC) with 2-sided significance level .05.
Results
Of the 2777 infants admitted to one of
the participating CNN NICUs from
January 1, 2010, through September 30,
2011, 447 infants were growth-restricted
fetuses according to fetal growth stan-
dards and 227 infants were growth
restricted according to neonatal growth
standards. After applying exclusion
606.e3 American Journal of Obstetrics & Gynecology DECEMBER 2018
criteria, 336 suspected growth-restricted
fetuses remained, of which 112 (33%)
were exposed to magnesium sulfate and
177 infants were growth restricted by
birthweight standards, of whom 61
(34%) were exposed to magnesium sul-
fate (Figure). All infants identified as
growth restricted by birthweight were
classified as growth-restricted fetuses
using fetal growth standards.
The maternal and neonatal charac-
teristics varied between growth-
restricted infants exposed and not
exposed to intrapartum magnesium
sulfate (Table 1). Significantly more
growth-restricted infants exposed to
ajog.org
magnesium sulfate had mothers with
hypertension, as well as fewer multiple
gestations in exposed infants, in both
growth restriction categories. Gesta-
tional age, prolonged rupture of mem-
brane, and cesarean deliveries were also
variable in growth-restricted fetuses as
defined by the fetal growth standard.
Table 2 shows aORs of common
neonatal morbidities. Intrapartum
magnesium sulfate was associated with
reduced odds of mortality, both in the
NICU and postdischarge. However, the
odds of intraventricular hemorrhage,
late-onset sepsis, bronchopulmonary
dysplasia, necrotizing enterocolitis, and
ajog.org OBSTETRICS Original Research

TABLE 1
Maternal and neonatal characteristics
Growth-restricted fetusesa Growth-restricted infantsb
Intrapartum Intrapartum Intrapartum Intrapartum
MgSO4 exposed, MgSO4 unexposed, MgSO4 exposed, MgSO4 unexposed,
Characteristics N ¼ 112 N ¼ 224 P value N ¼ 61 N ¼ 116 P value
Maternal characteristics
Maternal age, y, mean (SD) 31.6 (5.8) 30.6 (5.7) .14 31.6 (6.1) 30.9 (6.1) .47
Hypertension, n (%) 97 (86.6) 79 (35.6) <.01 54 (88.5) 48 (41.7) <.01
Prolonged rupture of 6 (5.5) 41 (18.8) <.01 5 (8.3) 13 (11.6) .50
membrane >24 h, n (%)
Antenatal steroids, n (%) 107 (96.4) 209 (94.1) .38 57 (95.0) 110 (96.5) .63
Cesarean delivery, n (%) 103 (92.0) 178 (79.5) <.01 57 (93.4) 98 (84.5) .09
Neonatal characteristics
Gestational age, wk, mean (SD) 26.8 (1.1) 26.5 (1.4) .04 26.5 (1.1) 26.6 (1.3) .83
Birthweight, g, mean (SD) 703 (143) 684 (139) .23 617 (1.6) 619 (108) .91
Male sex, n (%) 51 (45.5) 127 (56.7) .05 32 (52.5) 57 (49.1) .67
Multiple gestations, n (%) 16 (14.3) 65 (29.0) <.01 9 (14.8) 32 (27.6) .05
Apgar score <7, n (%) 45 (40.2) 95 (42.8) .65 27 (44.3) 49 (42.6) .83
SNAP-II score >20, n (%) 35 (32.1) 82 (37.3) .36 20 (34.5) 44 (38.6) .60
Receipt of chest compression 12 (10.7) 21 (9.4) .70 6 (9.8) 8 (6.9) .49
or epinephrine, n (%)
MgSO4, magnesium sulfate; N, number in category; n, number in group; SNAP-II, score for neonatal acute physiology.
a
Fetal growth standards define growth restriction as estimated birthweight <10th percentile; b Neonatal growth standards define growth restriction as birthweight <10th percentile.
Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.

severe ROP were not statistically signif- Comment Results in context

icantly different between the infants
exposed and unexposed to magnesium
sulfate.
Table 3 presents aORs for the primary
and secondary outcomes. Intrapartum
magnesium sulfate was associated with
significantly reduced odds of death or
sNDI in growth-restricted infants. Odds
of death or any NDI were not different
between groups. Rates of CP were lower
in growth-restricted fetuses exposed to
intrapartum magnesium sulfate; howev-
er, the adjusted odds were not different
between groups. BSID-III composite
motor scores were significantly higher in
magnesium sulfateeexposed group than
the unexposed group in both growth re-
striction categories. No significant dif-
ferences were seen in the adjusted
difference in mean of BSID-III composite
scores in cognitive and language skills
between those exposed and unexposed to
intrapartum magnesium sulfate.
Principal findings
In this population-based cohort study,
we identified that death or sNDI at
18e36 months’ corrected age was
significantly lower in growth-restricted
fetuses exposed to intrapartum mag-
nesium sulfate. The results were similar
whether we used fetal growth standards
or neonatal birthweight standards to
classify growth restriction. Corre-
spondingly, we identified higher com-
posite motor scores among magnesium
sulfateeexposed infants than unex-
posed infants. Mortality during NICU
admission and postdischarge was also
significantly lower in magnesium-
exposed infants than unexposed in-
fants. Finally, the majority of outcome
rates were lower in magnesium
sulfateeexposed growth-restricted fe-
tuses than unexposed; however, in
adjusted analyses there were no differ-
ences between the groups.
Our study is the first to specifically
evaluate the effects of intrapartum
magnesium sulfate in growth-restricted
fetuses. There have been 5 randomized
controlled trials evaluating the use of
intrapartum magnesium sulfate for
antenatal neuroprotection, but none of
them have specifically examined a sub-
group of growth-restricted fetuses.
Crowther et al5 evaluated the use of
intrapartum magnesium sulfate when
delivery was imminent in infants born at
<30 weeks’ gestation. They found a
statistically significant reduction in sub-
stantial gross motor dysfunction and
death or substantial gross motor
dysfunction but not in mortality, CP, and
combined death or CP at 24 months’
corrected age in infants exposed to
magnesium sulfate. The PREMAG trial7
assessed the effectiveness of intra-
partum magnesium sulfate in preventing
mortality, white-matter injury, or both

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Original Research OBSTETRICS ajog.org

TABLE 2
Neonatal outcomes of infants exposed to magnesium sulfate vs unexposed to magnesium sulfate
Growth-restricted fetusesa Growth-restricted infantsb
Intrapartum Intrapartum Intrapartum Intrapartum
MgSO4 exposed MgSO4 unexposed MgSO4 exposed MgSO4 unexposed
[N ¼ 112], [N ¼ 224], Adjusted ORc [N ¼ 61], [N ¼ 116], Adjusted ORc
Outcomes n (%) n (%) (95% CI) n (%) n (%) (95% CI)
Grade 1 or 2 IVH 27 (24.1) 55 (24.6) 1.02 (0.53e1.94) 10 (16.4) 22 (19.0) 0.54 (0.20e1.42)
Grade 3 or 4 IVH 8 (7.1) 26 (11.6) 0.55 (0.20e1.51) 6 (9.8) 14 (12.1) 0.68 (0.20e2.34)
Late-onset sepsis 30 (26.8) 72 (32.1) 0.89 (0.49e1.61) 16 (26.2) 45 (38.8) 0.71 (0.32e1.56)
BPD 53 (53.0) 100 (59.9) 0.84 (0.46e1.52) 32 (62.8) 55 (68.8) 1.10 (0.47e2.61)
NEC 7 (6.2) 32 (14.3) 0.38 (0.15e1.00) 5 (8.2) 11 (9.5) 0.57 (0.16e2.00)
Stage 3/4/5 ROP or 13 (11.6) 33 (14.7) 0.80 (0.34e1.88) 9 (14.8) 17 (14.7) 0.96 (0.34e2.73)
treated ROP
Mortality, both NICU 15 (13.4) 65 (29.0) 0.42 (0.19e0.95) 13 (21.3) 39 (33.6) 0.37 (0.15e0.95)
and postdischarge
BPD, bronchopulmonary dysplasia; CI, confidence interval; IVH, intraventricular hemorrhage; MgSO4, magnesium sulfate; N, number in category; n, number in group; NEC, necrotizing enterocolitis;
NICU, neonatal intensive care unit; OR, odds ratio; ROP, retinopathy of prematurity.
a
Fetal growth standards define growth restriction as estimated birthweight <10th percentile; b Neonatal growth standards define growth restriction as birthweight <10th percentile; c Adjusted for
gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension.
Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.

in infants born <33 weeks’ gestation.
They also reported a nonstatistically
significant reduction in neonatal mor-
tality, severe white-matter injury, and
combined outcome of severe white-
matter injury and/or mortality at
discharge in infants who received mag-
nesium sulfate. Rouse et al9 investigated
the effects of intrapartum magnesium
sulfate by rates of death at 12 months’
corrected age or moderate-severe CP at

24 months’ corrected age in infants
born between 24e31 weeks’ gestation.
They found that moderate or severe CP
occurred less frequently in infants
exposed to magnesium sulfate, but un-
like our study, the risk of death was
similar in infants exposed or unexposed
to magnesium sulfate. The Magpie trial6
was primarily designed to determine the
maternal effects of magnesium sulfate,
but also reported on neonatal outcomes.
They noted a lower risk of death or CP at
24 months’ corrected age in infants
exposed to magnesium sulfate, but again
the difference did not reach statistical
significance. Last, the findings of Mit-
tendorf et al8,28 are in contrast to both
our study and others. They reported
significantly higher pediatric mortality
rates, as well as adverse outcomes (a
composite of neonatal intraventricular
hemorrhage, periventricular leukoma-
lacia, CP, or death) in infants exposed
than unexposed to intrapartum magne-
sium sulfate at 18 months’ corrected age.
In 2009, 3 meta-analyses2e4 concluded
that magnesium sulfate given for fetal
neuroprotection reduced the risk of CP.
Our data add to the evidence showing
that intrapartum magnesium sulfate
could be safe and beneficial, even in
growth-restricted fetuses.
Our choice to use both fetal and
neonatal standards for growth restriction
highlights the difference in cut-offs used
by obstetricians and neonatologists. This
has been investigated previously in detail
with incidence of growth restriction
diagnosis approximately 20e25% by fetal
standards and 10% by neonatal stan-
dards.29 Results from both cut-offs in our
study pointed to similar results in out-
comes; however, it adds to ongoing
debate regarding the use of numerical
cut-off, outcome-based cut-off, local
population-based cut-off, universal cut-
off, or combined criteria30e33 for diag-
nosis of fetal/neonatal growth restriction.
Potential mechanism of action
The association of magnesium sulfate
with reduced sNDI fits with magnesium
sulfate’s role as a key mediator in
molecular pathways that regulate
apoptosis secondary to inflammation
and hypoxic-ischemic injury.34
Although the exact mechanism of mag-
nesium sulfate has yet to be elucidated,
hypotheses include blocking the N-
methyl-D-aspartate receptor, competi-
tively reducing entry of intracellular
calcium, modulating the actions of
proinflammatory cytokines and oxygen-
free radicals, and reducing vascular
instability thereby stabilizing blood
pressure and cerebral arterial
perfusion.34e36 Our study evaluated
intrapartum magnesium sulfate use
given for any indication. Our cohort was
born in 2010 and 2011 after the meta-
analyses2e4 were published, and during
the period the Canadian guidelines1
were published in 2011. Following pro-
fessional guidelines, it is not uncommon
for clinicians to administer the inter-
vention to all comers rather than exclu-
sively patients who were eligible in the
original clinical trials. Thus, it is imper-
ative to evaluate the impact of practices
in vulnerable subgroups to ensure the
practice does not lead to adverse conse-
quences. However, De Silva et al37
showed that overuse of magnesium sul-
fate for fetal neuroprotection to prevent
CP was not a significant problem.

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ajog.org OBSTETRICS Original Research

TABLE 3
Neurodevelopmental outcomes of infants exposed vs unexposed to magnesium sulfate
Growth-restricted fetusesa Growth-restricted infantsb
Intrapartum Intrapartum Intrapartum Intrapartum
Neurodevelopmental MgSO4 exposed MgSO4 unexposed Adjusted ORc MgSO4 exposed MgSO4 unexposed Adjusted ORc
outcomes [N ¼ 112], n (%) [N ¼ 224], n (%) (95% CI) [N ¼ 61], n (%) [N ¼ 116], n (%) (95% CI)
Death or sNDI 27 (24.1) 96 (42.9) 0.42 (0.22e0.80) 21 (34.4) 53 (45.7) 0.44 (0.20e0.98)
Death or any NDI 59 (52.7) 145 (64.7) 0.70 (0.40e1.24) 38 (62.3) 77 (66.4) 0.69 (0.32e1.50)
d
sNDI 12 (12.4) 31 (19.5) 0.46 (0.20e1.07) 8 (16.7) 14 (18.2) 0.53 (0.16e1.69)
d
Any NDI 44 (45.4) 80 (50.3) 0.84 (0.46e1.53) 25 (52.1) 38 (49.4) 0.87 (0.37e2.03)
Cerebral palsyd 6 (6.4) 11 (7.0) 1.67 (0.47e5.99) NRe NRe NRe
BSID-III 19 (20.7) 33 (23.4) 0.63 (0.29e1.39) 12 (26.1) 16 (22.5) 0.75 (0.25e2.24)
motord <85
BSID-III 14 (15.2) 23 (15.7) 0.59 (0.25e1.38) 10 (21.7) 15 (20.8) 0.66 (0.22e1.95)
cognitived <85
BSID-III 32 (34.8) 54 (38.6) 0.81 (0.42e1.56) 20 (43.5) 26 (38.2) 0.92 (0.38e2.24)
languaged <85
BSID-III 95 (90e100)f 95 (85e100)f 2.4 (e2.2 to 7.1)g 95 (85e100)f 90 (85e100)f 3.8 (e3.1 to 10.6)g
cognitive scored
BSID-III 94 (85e100)f 94 (85e97)f 4.7 (0.7e8.7)g 94 (82e100)f 91 (85e97)f 4.9 (0.2e9.6)g
motor scored
BSID-III, Bayley Scales of Infant and Toddler Development-third edition; CI, confidence interval; MgSO4, magnesium sulfate; N, number in category; n, number in group; NDI, neurodevelopmental
impairment; NR, not recorded; OR, odds ratio; sNDI, significant neurodevelopmental impairment.
a
Fetal growth standards define growth restriction as estimated birthweight <10th percentile; b Neonatal growth standards define growth restriction as birthweight <10th percentile;
c
Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension; d Only infants who received neurodevelopmental follow-up assessment; e Count in cell
<5etherefore, results are not reported to avoid identification of individuals according to network policy; f median score (interquartile range); g mean difference as calculated by linear regression
(95% CI).
Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.

Clinical implications
The fact that one third of our cohort
received magnesium sulfate indicates that
there was some awareness; however, there
is a need for improved knowledge trans-
lation. From our previous reports we
know that the rates of intrapartum mag-
nesium sulfate administration have
increased slowly from 40e65% over the
last 6 years.38 Our study supports the use
of intrapartum magnesium sulfate for
growth-restricted fetuses and suggests that
intrapartum magnesium sulfate use can
be reliably adopted for growth-restricted
fetuses; however, our sample size is small
and additional evaluation is required.
Research implications
Our results need to be confirmed in
further studies as our numbers are rela-
tively small. This is also evident from the
results of many of the secondary out-
comes, which indicate point estimate of
odds ratio being <1 but confidence
interval crossing 1. In addition, we also
need to study longer term neuro-
developmental outcomes at school age to
assess the safety of magnesium sulfate.
The majority of trials have evaluated
infants <32 weeks’ gestation and it may
be worthwhile to evaluate infants 29e32
weeks’ gestation in future studies.
Strengths and limitations
The strengths of this study include the
population-based cohort, robust data
collection, and detailed analysis of the
association of intrapartum magnesium
sulfate on neonatal morbidities and
neurodevelopment. We also analyzed
data by both pragmatic fetal standards
and stricter neonatal growth standards.
However, we acknowledge that our study
has several limitations. First, this was
retrospective observational study with a
relatively small sample size. However,
looking at the challenges of such trials,
we do not expect another large-scale trial
focused only on growth-restricted fe-
tuses. Second, we have w20% loss to
follow-up in our cohort. In our previous
reports we identified that those lost to
follow-up were somewhat larger and
more mature infants; however, it is
possible that attrition could have
impacted our results. However, there
was no differential loss of follow-up in 2
groups. Third, our database only con-
tains birthweight and does not collect
data on estimated fetal weight. We used
fetal growth standards and applied those
values to actual birthweight assuming
that if clinicians had estimated fetal
weight data they will correspond with
actual birthweight data. This assumption
could be challenged; however, we believe
that at population level our assumption
will hold true on average. Forth, we do
not have data on dose and duration of
magnesium sulfate in our database and
were therefore unable to quantify expo-
sure amount and duration. Fifth, we did

DECEMBER 2018 American Journal of Obstetrics & Gynecology 606.e6

Original Research OBSTETRICS
not collect reasons for lack of adminis- 4. Doyle LW, Crowther CA, Middleton P,
tration of magnesium sulfate, which may Marret S, Rouse D. Magnesium sulfate for
women at risk of preterm birth for neuro-
include extenuating circumstances, protection of the fetus. Cochrane Database Syst
imminent birth, or lack of knowledge of Rev 2009;1:CD004661.
the evidence for intrapartum magne- 5. Crowther CA, Hiller JE, Doyle LW,
sium sulfate use for growth-restricted Haslam RR; Australasian Collaborative Trial of
fetuses. Similarly, we also do not have Magnesium Sulfate Collaborative Group. Effect
of magnesium sulfate given for neuroprotection
indications for administration of mag- before preterm birth: a randomized controlled
nesium sulfate to mothers and could not trial. JAMA 2003;290:2669–76.
distinguish between the effect of mag- 6. Magpie Trial Follow-up Study Collaborative
nesium sulfate given for preeclampsia, Group. The Magpie Trial: a randomized trial
antenatal neuroprotection, or other comparing magnesium sulfate with placebo for
pre-eclampsia. Outcome for children at 18
reasons. Finally, although we adjusted months. BJOG 2007;114:289–99.
analyses for confounding variables, we 7. Marret S, Marpeau L, Zupan-Simunek V, et al.
cannot rule out unmeasured or residual Magnesium sulfate given before very-preterm
confounding. birth to protect infant brain: the randomized
controlled PREMAG trial*. BJOG 2007;114:
310–8.
Conclusion 8. Mittendorf R, Dambrosia J, Pryde PG, et al.
In conclusion, the administration of Association between the use of antenatal mag-
magnesium sulfate to women with nesium sulfate in preterm labor and adverse
growth-restricted fetuses immediately health outcomes in infants. Am J Obstet Gyne-
prior to preterm birth was associated col 2002;186:1111–8.
9. Rouse DJ, Hirtz DG, Thom E, et al.
with a reduced odds of death or sNDI at A randomized, controlled trial of magnesium
18e36 months’ corrected age for infants sulfate for the prevention of cerebral palsy.
born at <29 weeks’ gestation. n N Engl J Med 2008;359:895–905.
10. Mallard C, Loeliger M, Copolov D, Rees S.
Acknowledgment Reduced number of neurons in the hippocam-
pus and the cerebellum in the postnatal guinea-
The authors gratefully acknowledge all site in-
pig following intrauterine growth-restriction.
vestigators of the Canadian Neonatal Network
Neuroscience 2000;100:327–33.
(CNN), Canadian Neonatal Follow-up Network
11. Sasaki J, Fukami E, Mimura S, Hayakawa M,
(CNFUN), and Canadian Preterm Birth Network.
Kitoh J, Watanabe K. Abnormal cerebral
We would also like to extend our thanks to the
neuronal migration in a rat model of intrauterine
data abstractors of the CNN and CNFUN. Finally,
growth retardation induced by synthetic throm-
from the Maternal-Infant Care Research Center at
boxane A(2). Early Hum Dev 2000;58:91–9.
Mount Sinai Hospital, Toronto, Ontario, we thank
12. Ting JY, Kingdom JC, Shah PS. Antenatal
Junmin Yang, MSc, for statistical support; Sarah
glucocorticoids, magnesium sulfate, and mode
Hutchinson, PhD, for editorial support; and other
of birth in preterm fetal small for gestational age.
staff for organizational support.
Am J Obstet Gynecol 2018;218:S818–28.
13. Barbosa NO, Okay TS, Leone CR. Magne-
sium and intrauterine growth restriction. J Am
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Author and article information
From the Departments of Pediatrics (Dr Stockley and Dr
Shah) and Maternal-Fetal Medicine (Dr Kingdom) and the
Maternal-Infant Care Research Center (Dr Shah), Mount
Sinai Hospital, Toronto, Ontario; Department of Pediat-
rics, British Columbia Women’s Hospital, Vancouver,
British Columbia (Dr Ting and Dr Synnes); Division of
Maternal-Fetal Medicine, Department of Obstetrics and
Gynecology, McMaster University, Hamilton, Ontario (Dr
McDonald); Department of Obstetrics and Gynecology
and Department of Newborn and Developmental Paedi-
atrics, Sunnybrook Health Sciences Center, Toronto,
DECEMBER 2018 American Journal of Obstetrics & Gynecology
Original Research
Ontario (Dr Barrett); Department of Pediatrics, Saint John
Regional Hospital, Saint John, New Brunswick (Dr Mon-
terrosa); and Department of Pediatrics, University of
Toronto, Toronto, Ontario (Dr Shah); Canada.
*A complete listing of the network investigators can be
found in the Supplementary Information
Received Aug. 16, 2018; accepted Sept. 10, 2018.
No specific funding has been received for this study.
However, organizational support for the Canadian
Neonatal Network was provided by the Maternal-Infant
Care Research Center (MiCare) at Mount Sinai Hospital in
Toronto. MiCare and the Canadian Neonatal Follow-up
Network are supported by a Canadian Institutes of
Heath Research (CIHR) team grant (CTP 87518). MiCare
is also supported by the Ontario Ministry of Health and
Long-Term Care. The Canadian Preterm Birth Network is
supported by a CIHR team grant awarded to Dr Shah (PBN
150642). Dr McDonald is supported by a Tier II Canada
Research Chair. The funding agencies had no role in the
design of the study; collection, analysis, and interpreta-
tion of data; preparation and review of manuscript; or
decision to submit the manuscript for publication.
The authors report no conflict of interest.
Corresponding author: Prakesh S. Shah, MD, MSc.
prakeshkumar.shah@sinaihealthsystem.ca
606.e8